Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ ;31~7
This invention relates to novel chemical compounds and their
production. More particularly, this invention provides novel tetrahydro-
isoquinolines, processes for producing the compounds, novel intermediates
useful in making the compounds, and novel pharmaceutical compositions
containing the compounds useful for effecting desirable pharmacological
activity in animals.
According to one aspect of the subject invention there is
provided novel cyclopentano~l,2,3,4-tetrahydroisoquinolines of the formula:
':
OR
Formula 1
~ ORl
(C~12)m 1 ~;
¦ ~ C~12)n ~ ~;
N ~
R2 `, :
~ ~''' ' .
wherein R and Rl are the same or different lower alkyl groups containing 1
to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, penytl
and hexyl, R2 is hydrogen or a lower alkyl group having 1 to 6 carbon
atoms such as methyl or ethyl, m is an integer from 1 to 2, n is an
integer from 1 to 2 and m + n equals 3.
In another aspect of the present invention, there is provided
a process which comprises reacting a compound of the formula
~ OR
,:; .,
CHO
with a compound of the formula R2CH2NO2 to produce a compound of the
formula
. . . . . . . ..
1~63:L17 ` ~ :
OR
C ~ ORl ~.
N2
reducing said compound to a compound of the formula
- ~ OR
' OR
11'12
NH ~ C~l
2 \ .
R2 .~
reacting said compound with formaldehyde to produce a compound of the :
formula
ORl : .
1l~l2 1~l2
N
R2 - :
and then cyclizing said compound by acid to produce a compound of the `
formula
~ - la
~63~L17
(CH
H
R2
wherein R and Rl are the same or different lower alkyl groups, R2 is
hydrogen or a lower alkyl group, m is an integer from 1 to 2, n is an ;~ ;~
integer from 1 to 2 and m ~ n equals 3, and if desired converting said
compound to an acid addition salt. .
When m is 1 and n is 2 in Formula 1 the compounds can be
represented by Formula 2~
2' . 1' : :
3' ~ ~ OR ~ `
1 5 I . Formula 2 : .
~ -` ORl :
a 2 Id :
H
R2 ~'.. '
" ~:'
, ;,
~ - lb - ~ .
.. ,, :, ..
1063~L~17
wherein R, Rl and R2 have the significance previously assigned, and they
are named 5,6-dialkoxy-cyclopentano[h] 1,2,3,4-tetrahydroisoquinoline.
When m is 2 and n is 1 in Formula 1 the compounds can be rep- ;~
resented by Formula 3~
2' 3' ~ : :
OR
e~ ¦¦h Formula 3 . :~
C~
2 ~ :
R2 7 a .~
H ;
wherein R, Rl and R2 have the significance previously assigned, and they are
named 7,8-dialkoxy-cyclopentano [f]1,2,3,4-tetrahydroisoquinoline. ~-
To prepare the compounds o~ this invention, intermediate indanalde-
hydes o~ Formula 4 are ~irst prepared: ~ .
., ~ .
OR Formula 4 ~ '`
~ Rl ': '
~HO ~ :
in which the -CHO or aldehyde group, is in the 6 or 7-position.
The intermediate 7- or 8-indanaldehydes o~ Formula 4 can be pre- ~ ;
pared by reducing a 4,5-dialkoxy-1-indanone to 4,5-dialkoxyindane and then
converting that compound by means of a Friedel-Cra~ts reaction to a mixture
of 4,5-dialkoxy-6-indanaldehyde and 4,5-dialkoxy-7-indanaldehyde. This
series of reactions can be represented as follows:
:: - - . ~ . :
63~
.`... .. .
~ ' ~` '
~ > ~ / ~ OR
~ ORl i~ ~ :
CHO
wherein R and Rl have the previously assigned signi~icance. -
Among the starting materials which can be used in the described
sequence of reactions are 4,5-dimethoxy-1-indanone, 4,5-diethoxy-1 indanone,
4,5-dipropoxy-1-indanone and 4-methoxy-5-ethoxy-1-indanone. The publication
of John Koo in J. Am. Chem. Soc., 75, 1891 (1953) discloses 4,5-dimethoxy-1-
indanone. Other similar compounds, such as those Just named, can be pre-
pared by the procedure disclosed therein.
... ..
Reduction of the 4,5-dialkoxy-1-indanone can be readily achieved
catalytically usine hydrogen and a suitable catalyst such as palladium. The
hydrogenation is effected by placing the starting material in glacial acetic
acid containing the catalyst and a small a~ount of concentrated hydrochloric
acid. The hydrogenation proceeds readily at room temperature using a hydro-
gen pressure of about 25 to 100 psig. A~ter hydrogen uptake has ceased the
product can be recovered ~rom the reaction mixture by conventional methods.
Some 4,5-dialkoxyindanes which can be produced as described are
4,5-dimethoxyindane, 4,5-diethoxyindane, 4,5-dipropoxyindane, 4,5-diiso-
propoxyindane, 4,5-dibutoxyindane and 4-methoxy-5-ethoxyindane.
Formylation of a 4,5-dialkoxyindan according to the method of
Al~red Rieche et al. in Chem. Ber., 93, 88 (1960) using a Friedel-Cra~ts
catalyst such as stannic tetrachloride, aluminum trichloride or titanium
tetrachloride and ~ dichloromethyl methyl ether followed by water leads ~ ~
to the production of a mixture containing 4,5-dialkoxy-6-indanaldehyde and ~ ;
4,5-dialkoxy-7-indanaldehyde. The presence o~ a mixture of isomeric
aldehydes is shown by glc. A mixture of 4,5-dimethoxy-6- and -7-inaan-
- 3 - i
: ~ :,: .. . .. .. ... . .. ..
~C~63~7 ~ ;~
aldehydes formed by the described procedure contains about 75% of the 7~
formyl and 25% of the 6 formyl isomers. Obviously, the presence of other
alkoxy groups than the methoxy group could lead to different amounts of the
isomers in the resulting mixture.
The isomeric mixture of aldehydes obtained by the described process
is generally a liquid. Residual amounts of solvent are removed from the
liquid by distillation following which the product is distilled under high
vacuum to give a pure liquid mixture. Upon cooling, one of the isomeric
aldehydes crystallizes ~rom the liquid and is removed by filtration. Thus, ~ ;
4,5-dimethoxy-7-indanaldehyde crystallizes and leaves a liquid which is
primarily 4,5-dimethoxy-6-indanaldehyde. Fractional distil].ation of the
liquid gives the pure 6-formyl isomer.
Some of the separated purified aldehydes which can be prepared by
the described method are:
455-dimethoxy-6-indanaldehyde,
4,5-dimethoxy-7-indanaldehyde,
4,5-diethoxy-6-indanaldehyde,
4,5-diethoxy-7~indanaldehyde,
4,5-dipropoxy-6-indanaldehyde,
4,5-dipropoxy-7-indanaldehyde,
4-methoxy-5-ethoxy-6-indanaldehyde, and
4-methoxy-5-ethoxy-7-indanaldehyde.
Preparation of Formula 2 Compounds
The 5,6-dialkoxy-cyclopentano[h¦1,2,3,4-tetrahydroisoquinolines of -~
Formula 2 are prepared from the 4,5-dialkoxy-6-indanaldehydes by reacting
the aldehyde with a l-nitroalkane to produce a 4,5-dialkoxy-6-nitrovinyl-
indane, chemically reducing the nitrovinyl compound to the corresponding
aminoalkyl compound, reacting the resulting amine with formaldehyde to pro-
duce a Schiff's base and then treating the Schiff's base with acid to effect
a Pictet-Spengler acid catalyzed ring closure. This series of reactions can
be represented as follows:
- 4 -
~063~17 ~ ~
~R R2C~121102 ~ OX
ORl ORl .
CHO N02 C:H
2 1 :
~R RCHO [;~R EICl
~CR/ ~L CR~ 2
HN : :~
R2
wherein R, Rl and R2 have the previously assigned significance.
In effecting the first step of this series of reactions, nitro~
methane, nitroethane, l-nitropropane and other such l-nitroalkanes can be
used.
Condensation of the 4,5~dialkoxy-6-indanaldehyde with the nitro-
alkane can be readily effected by procedures discussed in Gairaud et al.,
J. Org. Chem., lo, 1 (1953) and particularly by the use of ammonium acetate
in glacial acetic acid at an elevated temperature. After cooling the reac-
tion mixture, the desired 4,5-dialkoxy-6-nitrovinylindane crystallizes from
solution and is separated by filtration.
By followine the described procedure there is obtained 4,5-
dimethoxy-6-nitrovinylindane, 4,5-dimethoxy-6-(2-nitro-2-methylvinyl)indane
4,5-dimethoxy-6-(2-nitro-2-ethylvinyl)indane, 4,5-diethoxy-6-nitrovinyl-
indane, 4,5-diproproxy-6-nitrovinylindane and 4-methoxy-5-ethoxy-6-nitrovinyl-
indane.
The 4,5-dialkoxy-6-nitrovinylindanes are readily reduced chemically
- 5 -
'
~0631~ :
by means of lithium aluminum hydride in dry ether according to the method of'
Marchant et al., J. Chem. Soc. 327 (lg56) to produce -the desired 4,5-
dialkoxy-6-aminoethylindanes. Some of' the compounds which are produced in
this way are 4,5-dimethoxy-6-aminoethylindane, 4,5-diet;hoxy-6-(2-~minopropyl)~
indane, 4,5-dipropoxy-6-(2-aminobutyl)indane and 4-methoxy-5-ethoxy-6-amino-
ethylindane. ~ '
The 4,5-dialkoxy-6-aminoethylindanes are converted to the Schi~f's
bases by reaction with formaldehyde using conventional reaction conditions
f'or preparing Schiff's bases. Some o~ the compounds so produced are N-
methylidene-4,5-dimethoxy-6-(2-aminoethyl)indane, N-methylidene-4,5-diethoxy-
6-(2-aminopropyl)indane, N-methylidene-4,5-dipropoxy-6-(2-aminobutyl)indane
and N-methylidene-4-methoxy-5-ethoxy-6-(2-aminoethyl)indane.
The described Schif'~'s bases are readily cyclized in aqueous acid,
such as 23% hydrochloric acid, at a moderately elevated temperature of' about
40 to 75 C., to the cyclopentano[h~l,2,3,4-tetrahydroisoquinolines. The
product is readily recovered by evaporation o~ the solvent and acid.
Representative cyclopentano[h]l,2,3,4-tetrahydroisoquinolines
which are produced as described are 5,6-dimethoxy-cyclopentano[h]1,2,3,4-
tetrahydroisoquinoline, 5~6-diethoxy-cyclopentano[h]1,2~3,4-tetrahydro
isoquinoline, 5,6-dipropoxy-cyclopentano[h]1,2,3,4-tetrahydroisoquinoline ~ ;
and 5-methoxy-6-ethoxy-cyclopentano[h]1,2,3,4-tetrahydroisoquinoline.
Preparation of' Formula 3 Compounds
The 7,8-dialkoxy-cyclopentano[f']1,2,3,4-tetrahydroisoquinolines o~
Formula 3 are prepared from the 4,5-dialkoxy--7-indanaldehydes by reacting
the aldehyde with a l-nitroalkane to produce a 4,5-dialkoxy-7-nitrovinyl-
indane, chemically reducing the nitrovinyl compound to the corresponding
aminoalkyl compound, reacting the resulting amine with f'ormaldehyde to pro-
duce a Schif'f's base and then treating the Schi~f's base with acid to ef'~ect
a Pictet-Spengler acid catalyzed ring closure. This series o~ reactions can
be represented as ~ollows:
- 1063~7 ~ ~
_ 2 2 ~ C ~ OR
/C
R2 N2
i .~;
~ ~ 1 2~ OR
R2 1IR2 ~ ~[OR
2 N
H
. ~ .
wherein R, Rl and R2 have the previously assigned significance.
In effecting the first step of this series of reactions, ni-tro- ~
methane, nitroethane, l-nitropropane and other such l-nitroalkanes can be ~ ?
used.
Condensation of the 4,5-dialkoxy-7-indanaldehyde with the nitro-
alkane can be readily effected by procedures discussed in Gairaud et al.,
J. Org. Chem. 18, 1 (1953) and particularly by the use of ammonium acetate in
glacial acetic acid at an elevated temperature.
10By following the described procedure there is obtained 4,5-
dimethoxy-7-nitrovinylindane, 4,5-dimethoxy-7-(2-nitro-2-methylvinyl)indane, ~ ~-
4,5-dimethoxy-7-(2-nitro-2-ethylvinyl)indane, 4,5-diethoxy-7-nitrovinyl-
indane, 4,5-dipropoxy-7-nitrovinylindane and 4-methoxy-5-ethoxy-7-nitro-
vinylindane.
The 4,5-dialkoxy-7-nitrovinylindanes are readily reduced chemically
by means of lithium aluminum hydride in dry ether according to the method of
Marchant et al., J. Chem~ Soc. 327 (1956) to produce the desired 4,5-
- 7 -
~' ~ '' ' '" ' .
~a~6 3~ 17 ! i
dialkoxy-7-aminoethylindanes. Some of the co~pounds which are produced in
this ~lay are 4,5-dirnethoxy-7-aminoethylindane, 4,5-diethoxy-7-(2-amino-
propyl)indane, I~,5-dipropoxy-7-(2-aminobutyl)indane and 4-methoxy-5-ethoxy-
7-aminoethylindane.
The 4,5-dialkoxy-7-aminoethylindanes are converted to the Schiff's
bases by reaction with formaldehyde using conventional reaction conditions
for preparing Schiff's bases. Some of the compounds so produced are N-
methylidene-4,5-dimethoxy-7-(2-aminoethyl~indane, N-methylidene-4,5-diethoxy-
7-(2-aminopropyl)indane, N-methylidene-4,5-dipropoxy-7-(2-aminobutyl)indane
and ~-methylidene-4-methoxy-5-ethoxy-7-(2-aminoethyl)indane.
The described Schif`f's bases are readily cyclized in aqueous acid,
such as 23% hydrochloric acid, at a moderately elevated temperature of about
40 to 75C., to the cyclopentano[f]l,2,3,4-tetrahydroisoquinolines. The
product is readily recovered by evaporation of the solven-t and acid.
Representati~e cyclopentano[~]l,2,3,4-tetrahydroisoquinolines which
are produced as described are 7,8-dimethoxy-cyclopentano[f]1,2,3,4-tetra-
hydroisoquinoline, 7,8-diethoxy-cyclopentano[f]1,2,3,4-tetrahydroisoquino-
line, 7,8-dipropoxy-cyclopentano[f]1,2,3,4-tetrahydroisoquinoline and 7-
methoxy-B-ethoxy-cyclopentano[f]1,2,3,4-tetrahydroisoquinoline.
The 5,6-dialkoxy-cyclopentano[h]1,2,3,4-tetrahydroisoquinolines
and 7,8-dialkoxy-cyclopentano[f]1,2,3,4-tetrahydroisoquinolines, being
amines, can be converted to acid addition salts by contacting the amines
with a suitable inorganic acid such as hydrochloric acid, sulfuric acid,
phosphoric acid and hydrobromic acid or an organic acid such as citric acid, `
acetic acid, formic acid, malic acid, fumaric acid, succinic acid, benzoic
acid and tartaric acid.
The 5,6-dialkoxy-cyclopentano[h]1,2,3,4-tetrahydroisoquinolines
and the 7,8-dialkoxy-cyclopentano[f]1,2,3,4-tetrahydroisoquinolines are use-
ful as neutralizing agents since they are bases which form salts with acids. ;~
According to a second aspect of the invention, the 5,6-dialkoxy-
cyclopentano[h]l,2,3,4-tetrahydroisoquinolines and the 7,8-dialkoxy-cyclo-
pentano[f]l,2,3,4-tetrahydroisoquinolines are also useful pharmaceu-tically.
- 8 -
. ,, ,: , . .. . . .
)63JL17
`~ ' '':`. , ,
These compounds when administered to animals intraperitoneally or orally
exert an anti-hypertensive effect. The compounds thus can be used to reduce
blood pressure.
The amount of active ingredient administered may be varied; how-
ever, it is necessary that the amount of active ingredient be such that a
suitable dosage is given. The selected dosage depends upon the desired
therapeutic effect and on the duration of -treatment. Dosages of from 0.1 to
25 mg./kg. of body weight daily, preferably in divided doses, i.e.~ three to
four times daily, can be administered.
The active agents of this invention can be administered to animals,
including humans, as pure compounds. It is advisable, however, to first ;~
combine one or more of the compounds with a suitable pharmaceutical carrier ;
to attain a satisfactory size to dosage relationship and thereby obtain a
pharmaceutical composition.
Pharmaceutical carrlers which are liquia or solid can be used.
Solid carriers such as starch, sugar, talc and the like can be used to form
powders. The powders can be used for direct administration or they may be
used to make tablets or to fill gelatin capsules. Suitable lubricants like
magnesium stearate, binders such as gelatin, and disintegrating agents like
sodium carbonate in combination with citric acid can be used to form tablets. ;~
Sweetening and flavoring agents can also be included.
Unit dosage forms such as tablets and capsules can contain any
suitable predetermined amount of one or more of the active agents, and they
may be administered one or more at a time at regular intervals. Such unit
dosage forms, however, should generally contain a concentration of 0.1 to 50
percent by weight of one or more of the active compounds. Unit dosage form~,
such as tablets and capsules, can contain about 2 to 300 mg. of active agent. ; `
A typical tablet can have the composition: ~
~, ~ ;' '
,`~ ' ' ''.' ' ':
Active agent (1) 100
Starch U.S.P. 57
Lactose U.S.P.73
_ g_
:
.. : :,
:~ :
:.~. . .
~63~
Mg
Talc. V.S.P. 9
Stearic acid 12 ~;~
(1) 7,8-dimethoxy-cyclopentano[f]1,2,3,4-tetrahydro- ~;
isoquinoline HCl or 5,6-dimethoxy-cyclopentano
[h]1,2,3,4-tetrahydroisoquinoline HCl
The compounds of Formulas 2 and 3 exhibit both oral and parenteral
activity and accordingly can be formulated in dosage forms for either oral or
parenteral administration to a patient.
Solid dosage forms for oral administration include capsules, tab- ~
lets7 pills, powders, granules and the like. ~ ;
Liquid dosage forms for oral administration include emulsions,
solutions, suspensions, syrups and the like containing diluents commonly used
in the art, such as water. Besides inert diluents, such preparations can
also include ad~uvants such as wetting agents, emulsifying and suspending
agents and sweetening, flavoring and perfuming agents.
Preparations for parenteral administration include sterile aqueous
or non-aqueous solutions. Examples of non-aqueous solvents or vehicles are
propylene glycol, polyethylene glycol, vegetable oils such as olive oil and
in~ectable organic esters such as ekhyl oleate. The parenteral preparations
are sterilized by conventional methods.
5,6-dimethoxy-cyclopentano~h]1,2,3,4-tetrahydroisoquinoline base
has an ALD50 in mice of 25 mg/kg intraperitoneally. When administered at 5
to 10 mg/kg ip to hypertensive rats a significant lowering of systolic blood
pressure results although the 10 mg/kg dose heralded approach to a toxic
level. In the anesthetized normotensive dog, a dose of 2-4 mg/kg iv lowered
the mean blood pressure 71% with a 50% return in pressure after 6 minu-tes. ~ -
7,8-dimethoxy-cyclopentano[f]1,2,3,4-tetrahydroisoquinoline ~Cl has
an ALD50 in mice of 79-89 mg/kg intraperitoneally. When administered at 10
to 20 mg/kg ip to hypertensive rats significant lowering of systolic blood -
pressure results. In the anesthetized normotensive dog, a dose of 2 to 6.6
mg/kg iv lowered the mean blood pressure 48% with a 50% return in pressure
after 11 minutes.
- 10 - ; ,, ~,,
.. . . .
,
~063~17
The following examples are presented to further illustrate the
invention.
Example 1
4,5-Dimethoxyindane
A mixture of 52.6 g (0.275 mole) of 4,5-dimethoxy-1-indanone, 3.00
g of 5% Pd/C, 100 ml of glacial acetic acid and 20 drops of conc. HCl was
hydrogenated at 45 psi and room temperature until hydrogen uptake ceased.
Following filtration of the used catalyst, two methods were used to work up
the reaction.
A. The acid was neutralized with dilute sodium hydroxide and the ` ~ !
product extracted from the aqueous phase with ether. The ether was removed
by distillation and crude 4,5-dimethoxyindane was distilled under reduced
pressure, b.p. 133-135C (15 mm) yielding 42.0 g (~6.4%) of clear liquid.
Infrared analysis showed the absence of carbonyl absorption.
B. Most of the acetic acid was removed on the ro-tary evaporator
: : i
and the remaining liquid was dis-tilled as before giving 4,5-dimethoxyindane
.: .
with no significant difference in yield from that obtained in A.
Example 2
4,5-Dimethoxy-7-indanaldeh~de
To a solution of 10.0 g (o.o56 mole~ of 4,5-dimethoxyindane, 24.0
g (0.126 mole) of titanium tetrachloride and 104 ml of CH2C12 in a 250 ml 3-
necked flask fitted wi-th a thermometer and condenser and magnetically
stirred, 11.0 g (o.og6 mole) of ~,~-dichloromethyl methyl ether was added
rapidly dropwise at 0~. Hydrogen chloride gas was liberated during the ~ ;course of the reaction. After vigorous evolution of XCl had subsided, the
reaction solution was allowed to slowly warm to room temperature and it was ~
stirred for 1 to 2 hours. The solution was refluxed for 6 hours, cooled and ~ ;
the reaction mixture was poured over 200 ml of ice and water (ether and salt
were added at this point to increase the volume of the organic phase, to
invert the two layers and to break emulsions). The organic phase was washed
.~. ~ . . .
with 2 x 100 ml of ô% ~aHC03 solution, 1 x 100 ml of water and dried over ;
~a2S04. After removal of the solvent by distillation, the mixture of
- 11 -
: . .,:, , : , ~
11~631~7
aldehyde isomers was distilled under high vacuum (b.p. 115-126C; 0.28 mm)
giving 10.2 g of the 6- and 7-position aldehydes (88~). The 7-position
aldehyde which crystallized from the liquid was filtered. This process was
repeated several times by seeding the filtrate followed by cooling. Gas
chromatography showed the white crystalline solid 4,5-dimethoxy-7-indanalde-
hyde to be one component of the two component mixture. In this way 4.24 g of
white solid was ob-tained, m.p. 41-44C, yield 38.5%. Anal. Calcd. for
C12H1403: C, 69.88; H, 6.84. Found: C, 70.03; H, 6.66.
Example 3
4,5-Dimethoxy-7-nitrovinylindane
To a 100 ml 3-necked round bottom flask fitted with a condenser and
thermometer and magnetically stirred, was added 12.97 g (0.063 mole) of 4,5-
dimethoxy-7-indanaldehyde, 3.00 g (0.039 mole) of ammonium acetate, 13.0 ml
(0.292 mole) of CH3N02 and 40 ml of glacial acetic acid. This mixture was
heated for 1 to 2 hours at 112C. As the reaction solution began to cool the
entire solution solidified. After cooling in an ice bath and removing the
solvent by filtration, the solid 4,5-dimethoxy-7-nitrovinylindane was washed
with a small volume o~ ace-tic acid giving fine yellow needles (9.55 g) after
thorough drying. The filtrate was poured into 300 ml of ice and water from
which precipitated a slightly gummy, yellow-brown solid. This gave an addi-
tional 1.43 g of crystalline solid after drying and crystallizing from
methanol giving a total yield of 10.98 g (70%). An analytical sample melted
at 128-130 C. Anal. Calcd. for C13H15~04: C, 62.64; H, 6.o6; ~, 5.62. ~ -s
Found: C, 62.79; H, 6.12; N, 5.53.
Example 4
4,5-Dimethoxy-7-aminoethylindane
To a slurry of 15.0 g (0.395 mole) of LiAlH4 and 500 ml of anhyd-
rous ether in a 5 liter 3-necked flask fitted with a condenser, mechanical
stirrer and dropping funnel was added 20.0 g (o.o84 mole) of 4,5-dimethoxy-
7-nitrovinylindane dissolved in 2 liters of ether. The addition was made
over a period of about 4 hours while refluxing the ether slurry. When the
addition was completed, refluxing was continued for an additional 1 to 2
- 12 -
- ~. . ~ , . , - , .. ~ :
1~631~'7
hours. After the addition of 20 g of diatomaceous earth and then 70 ml of
water slowly, dropwise, with cooling in an ice bath, the supernatant ether
was decanted, the salts were washed with fresh ether several times followed
by decantation and finally filtration. The solvent was removed by distilla~
tion and more thoroughly on a rotary evaporator. Cooling in an ice bath
gave 15.91 g (90%) of 4,5-dimethoxy-7-aminoethylindane as a slightly yellow ?
solid, m.p., 45-48C. High vacuum distillation gave an analytical sample.
Anal. Calcd. for C13HlgN02: C, 70.55; H, 8-65; N, 6-32- Found: C~ 70-22;
H, 8.49; N, 6.18.
Example 5
7,8-Dimethoxy-cyclopentano[f]1,2,3,4-tetra-
hydroisoquinoline Hydrochloride
To 11.1 ml of formalin in a round bottom flask heated at 60-70C
and magnetically stirred was added 10.95 g (0.049 mole) of 4,5-dimethoxy-7-
aminoethylindane (dissolved in 22 ml of methanol) rapidly dropwise. After
heating 50 min., the solvent was thoroughly removed on a rotary evaporator.
The ir spectrum showed absence of primary amine stretchine vibrations at
3190, 3300, 3370 with a weakening in intensity of the peak at 1605 cm 1.
The N-methylidene-4,5-dimethoxy-7-(2-aminoethyl)indane was dissolved in 55 -
ml of 23% HCl and heated on a water bath with stirring at 50-60C for 30 `~ j
minutes. The water-acid solvent was removed on the evaporator and the
residue was dried overnight in a vacuum oven giving a hard solid which
yielded 11.14 g (84.1%) of 7,8-dimethoxy-cyclopentano[f]1,2,3,4-tetrahydro-
isoquinoline when crystallized from acetonitrile-absolute alcohol, m.p.
232-235C dec. Anal. Calcd. for C14H20N02Cl: C, 62.33; H, 7.47; N, 5.19;
Cl, 13.14. Found: C, 62.58; H, 7.36, N, 5.33; Cl, 13.29. j ~
Example 6 ~ ;
'` - ::- .' '
4,5-Dimet oxy-6-indanaldehyde
The 4,5-dimethoxy-6-indanaldehyde was obtained by high vacuum
(20-50~) fractional distillation of the mixture of aldehydes remaining after
repeated crystallization and filtering off of the 7-aldehyde in Example 2.
The 6-aldehyde distilled as a pure substance in the first fractions followed
by a mixture of the aldehydes and finally the pure 7-aldehyde. The 4,5-
- 13 -
- .
.: . . : .
, :. . ~ : ................ :. . .
~63~
dimethoxy-6-indanaldehyde was a liquid at room temperature but crystallized
when refrigerated. An approximate m.p. (11C) was obtained from the temper-
ature of a mixture of the solid in equilibrium with the liquid. Anal. Calcd.
for C12H1403: C, 69.88; H, 6.84. Found: C, 70.13; H, 6.87.
Example 7
4,5-Dimethoxy-6-nitrovinylindane
In a 2 liter 3-necked ~lask fitted with a condenser and thermometer
and magnetically stirred, 126.7 g (0.613 mole) of 4,5-dimethoxy-6 indanalde-
hyde, 29.3 g (0.380 mole) of ammonium acetate, 127 ml (2.82 mole) of nitro-
methane and 390 ml of acetic acid were heated at 112 C for 45 minutes. After -
cooling in the refrigerator and scratching with a glass rod the solution
crystallized. After filtering and washing with cold acetic acid the product
was dried under vacuum overnight and recrystallized from me-thanol yielding
104.4 g (68%) of 4,5-dimethoxy-6-nitrovinylindane as yellow needles, m.p.
103.5-104.5C. Anal. Calcd. for C13H15N04: C, 62.64; H, 6.o6; N, 5.62
~ound: C, 62.45, E, 6.17; N, 5.84.
Example 8
4~5-Dimethoxy-6-aminoethylindane -
: . ~ :
,~ . ;
To 9.2 g (0.242 mole) LiAlH4 in 400 ml of anhydrous ether was added
20 12.17 g (o.o48 mole) of 4,5-dimethoxy-6-nitrovinylindane in 1 liter of
anhydrous ether dropwise over a period of 4 hours while refluxing; this was
followed by refluxing for a further 2 ho~urs. Af-ter adding 15 g of diato-
maceous earth and decomposing excess LiAlH4 with 40 ml of H20 (while cooling
in an ice bath), the ether was decanted and the salts were washed twice with
ether followed by decantation and finally filtering. The ether was removed
by distillation and the 4,5-dimethoxy-6-aminoethylindane was distilled yield-
ing 7.42 g (68%), b.p. 101-103C (75~). Anal. Calcd. for C13HlgN02:
C~ 70.55; H, 8.65; N, 6.32. Found: C, 70.68; H, 8.71, N, 6.35.
Example 9
5,6-Dimethoxy-cyclopentano~h]1,2,3,4-tetra-
hydroisoquinoline Hydrochloride
To 7.42 ml of formalin in a 100 ml boiling flask was added dropwise
7.42 g (0.033 mole) of 4,5-dimethoxy-6-aminoethylindane in 15 ml of methanol
- 14 -
,~
. .
~1~63117
with magnetic stirring and warming. After heating at 70-75C for 45 minutes, ~ ?
the mixture was rinsed into a separatory funnel with 3 x 50 ml of benzene.
The benzene layer was washed with 3 x 100 ml of water and then the benzene
was thoroughly removed on the evaporator. ~he ir spectrum showe~ absence of
NH stretching and wea~ening of intensity of the band at 1576 cm 1. The N-
methylidene-4,5-dimethoxy-6-(2-aminoethyl)indane weighed 8.72 g and was dis-
solved in 39 ml of 23% HCl followed by heating at 50-60C for 30 minutes.
The aqueous acid was removed on the rotary evaporator yeilding an oily,
viscous substance which was dried in a vacuum oven in the presence of P205.
10 A tacky hygroscopic solid was obtained which was crystallized from ether-
ethanol giving fine needles, m.p. 215.5-216.5C. Further experimentation
showed acetonitrile-ethanol to be a better recrystallization solvent.
Anal- Calcd- for cl4H2oNo2cl: C, 62.33; H, 7.47; N, 5.19; C1, 13.11~.
Found: C, 62.47; H, 7.33; N, 5.15; Cl, 13.36.
The foregoing detailed description has been given for clearness of ~ ,
understanding only, and no unnecessary limitations should be understood ~ ;
therefrom, as modifications will be obvious to those skilled in the art. `
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